Early events in the development of breast cancer engage a network of regulatory factors, some of cancer and some of host origin. Understanding the complexity of that network requires the experimental efforts of immunologists, endocrinologists, biochemists, cell biologists, molecular biologists and pathologists. The three projects that comprise this interactive R01 Program utilize in vivo murine and human xenograft models, in vitro murine and human cell systems and clinical samples of proliferative, high risk lesions of the human breast to focus on the critical events that occur during the progression of preneoplastic (high risk) lesions to overt breast cancer. This first R01 in the series builds upon extensive data showing that progression of the preneoplastic, C4 hyperplastic alveolar nodule (HAN) mouse line to tumor is positively associated with NK cell function and, further, that both progression and T-cell/NK function are under prolactin (PRL) control. Specific aims address the respective roles of T and NK cells, and of their lymphokine products, in progression and test hypotheses about the specific nature of the PRL-T/NK - breast epithelial cell link. The 2nd, R01 investigates the molecular, cellular and tissue mechanisms of immunologically driven breast cancer progression. These two R01 's also bridge the work on mouse systems with similar investigations utilizing a newly developed, human in vitro and xenograft model of high risk. The third R01 translates the findings of the other two into the clinical arena by utilizing fresh sample of proliferative lesions and early breast cancer as well as a tissue collection from women at high risk to develop breast cancer and for whom the outcome of that risk is known. Both the human model and the tissue collection have been developed by researchers within the Breast Cancer Program of the Meyer L. Prentis Comprehensive Cancer Center of Metropolitan Detroit, and are therefore unique resources of that Program.